Lactam formation by a selective cyclization process

ABSTRACT

This invention provides a process for preparing lactams, by selectively reacting a novel 1-hydrocarbyl-amino (or heteroatom-substituted hydrocarbylamino); 1,1-dicarboxylic acid, alkylesters; 1-hydrocarbyl (or heteroatom-substituted hydrocarbyl) carboxylic acid, alkyl ester methane, as the salt of an acid having a pKa of 0 or more, in the absence or presence of a base, whereby novel lactams wherein one or both hydrocarbyl moieties are incorporated into the lactam ring are obtained. That is, the acid moiety of said novel salt promotes the reaction whereby both hydrocarbyl moieties are incorporated into the ring, while the presence of a base, in an amount substantially equivalent to said acid promotes the reaction whereby only one hydrocarbyl is incorporated into the ring.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a process for preparing lactams. Inparticular, the present invention provides a process for selectivelyreacting a novel 1-hydrocarbylamino (or heteroatom-substitutedhydrocarbylamino); 1,1-dicarboxylic acid, alkylesters; 1-hydrocarbyl (orheteroatom-substituted hydrocarbyl) carboxylic acid, alkyl estermethane, as the salt of an acid having a pKa of 0 or more, to providenovel lactams wherein one or both hydrocarbyl moieties are incorporatedinto the lactam ring. Preferably, The selectivity of the reaction iscontrolled by either cyclizing the novel salts, in the absence of abase, or cyclizing said novel salts, in the presence of an amount ofbase substantially equivalent to said acid. That is, the acid moiety ofsaid novel salt promotes the reaction whereby both hydrocarbyl moietiesare incorporated into the ring, while the presence of a base promotesthe reaction whereby only one hydrocarbyl is incorporated into the ring.Therefore, reaction at neutral or slightly basic conditions providesimproved selectivity to lactams having a smaller ring size, while theacid-catalyzed reaction increases the selectivity to lactams having alarger ring size.

2. Description of the Art

Lactams are cyclic amides having many uses as intermediates for thepreparation of polymers, medicinals, etc. In particular, in medicinaluses, certain lactams have been found to enhance the transdermalpenetration of various physiologically-active compounds into the tissuesand blood stream of an animal, e.g. a human. See, for example, U.S. Pat.Nos. 3,989,816; 4,316,893; 4,310,525; 4,422,970; and 4,405,616; whereinlactams, in particular, having 1-n-alkyl azacycloalkan-2-ones, having aring size of from 5 to 9 members are shown to enhance the transdermalpenetration of physiologically-active materials. It has been found thatboth the size of the ring and the length of the n-alkyl group affectsthe transdermal penetration-enhancing properties of the1-n-alkylazacycloalkan-2-ones disclosed in these patents. Thus, it wouldbe desirable to have a process for selectively varying both the ringsize and the length of the n-alkyl group as well as preparing novelsubstituted lactams for penetration enhancement. Lactams are also usefulin the preparation of nylon 6-type polymers wherein the propertiesthereof may be systematically modified through the regulation of thenature and position of the lactam substituent. See, for example, C. G.Overberger et al., Journal of Polymer Science, Vol. 10, 2265-2289(1972).

SUMMARY OF THE INVENTION

It has unexpectedly been found that a novel 1-hydrocarbyl-amino (orheteroatom-substituted hydrocarbylamino); 1,1-dicarboxylic acid, alkylesters; 1-hydrocarbyl (or heteroatom-substituted hydrocarbyl) carboxylicacid, alkyl ester methane, as the salt of an acid having a pKa of 0 ormore, may be selectively cyclized into a lactam, having either one orboth of the hydrocarbyl moieties incorporated into the ring, by firstneutralizing said acid with a substantially equivalent amount of baseand then carrying out said cyclization process or cyclizing the acidsalt without neutralization, respectively.

DESCRIPTION OF THE INVENTION

The present invention provides a process for converting a first compoundrepresented by the general formula: ##STR1## selectively into a secondcompound represented by the general formula: ##STR2## or into a secondcompound represented by the general formula: ##STR3## by cyclizing saidfirst compound in the absence of a base or by neutralizing said compoundwith an amount of base substantially equivalent to A (A represents aweak acid, i.e. an acid having a pKa of 0 or more) and then cyclizingsaid first compound. Thus, either the hydrocarbyl moiety represented byR or both R and the hydrocarbyl moiety represented by R² (with theexception noted below) may be incorporated, selectively, into theresulting lactam ring by carrying out the cyclization in the absence orpresence of a base.

This reaction is general in nature, provided the first compound has thestructure represented by the above general formula, wherein R and R²each represent a divalent hydrocarbyl radical or a hydrocarbyl radicalsubstituted with one or more hetero atoms selected from the groupconsisting of oxygen, nitrogen, sulfur, phosphorus and halogen atoms;and R¹ is an alkyl radical having from one to eight carbon atoms.Preferably, R and R² are selected from the group consisting of alkyl,alkenyl and heteroatom-substituted alkyl or alkenyl radicals. Morepreferably, R is selected from radicals represented by the generalformula

    --CR.sup.3.sub.2).sub.x

wherein R₃ is selected from the group consisting of hydrogen, alkylradicals having from one to six carbon atoms and phenyl and x is aninteger of from 1 to 5, and R² is preferably selected from radicalsrepresented by the general formula

    --CR.sup.4.sub.2).sub.y

wherein R⁴ is selected from the group consisting of hydrogen, alkylradicals having from one to six carbon atoms and phenyl and y is aninteger of from 2 to 5.

It has been found that when R² represents a divalent hydrocarbon radicalhaving more than two carbon atoms between the carboxy carbon atom andthe methane carbon atom then incorporation of R² into the lactam ringdoes not occur even when the cyclization is carried out in the absenceof a base. Therefore, for the preparation of amides wherein R² isincorporated into the lactam ring R² is selected from radicalsrepresented by --CR⁴ ₂)_(y) above wherein y is 1 or 2.

For the purpose of selectivity to a larger or smaller ring size, evenmore preferably, R³ and R⁴ are hydrogen radicals, x is 2 and y is 1 or2.

Most preferably, R¹ is ethyl, and y is 1.

A represents a weak acid, i.e. an acid having a pKa of 0 or more;preferably 2 or more. Suitable acids include carboxylic acids havingfrom one to ten, more preferably from one to six carbon atoms, e.g.acetic acid and propionic acid. Halogenated carboxylic acids, e.g.fluorinated and chlorinated carboxylic acids, such as trichloroaceticacid and trifluoroacetic acid are also suitable.

Thus, 1-ethylamino, 1,1-dicarboxylic acid, ethylester,1-methylcarboxylic acid, ethyl ester methane and 1-ethylamino,1,1-dicarboxylic acid, ethyl ester, 1-ethylcarboxylic acid, ethyl estermethane may be selectively converted into a 6-membered lactam or a5-membered lactam and a 7-membered lactam or a 5-membered lactam,respectively.

In particular, the 7-membered lactam resulting from the cyclization of1-ethylamino, 1,1-dicarboxylic acid, ethyl ester, 1-ethyl carboxylicacid, ethyl ester methane, is useful as an intermediate forpenetration-enhancing agents of varying hydrophilicity (e.g. carboxylicacid-substituted alkyl lactams) and nylon 6-type polymers as well asmedicinal agents.

The 6-membered lactam resulting from the cyclization of 1-ethylamino,1,1-dicarboxylic acid, ethyl ester, 1-methyl carboxylic acid, ethylester methane is useful as an intermediate for penetration-enhancingagents of varying hydrophilicity (e.g. carboxylic acid-substituted alkyllactams) and nylon 6-type polymers as well as medicinal agents.(Moreover, as discussed below, this representative first compound may becyclized to the 6-membered lactam at 97 percent selectivity.)

The base may be selected from the group consisting of Group I and IImetal oxides, hydroxides and carbonates or any other compound or saltwhich provides a pH greater than 7 when contacted with the above-definedfirst compound. For example, sodium hydroxide, potassium hydroxide,sodium oxide, potassium oxide, calcium oxide, calcium hydroxide, calciumcarbonate, are suitable bases for the process of the present invention.

The cyclization process is varied in accordance with the desire toobtain lactams having one or both hydrocarbyl groups, represented by Rand R², above, incorporated into the ring. To obtain the lactams havinga larger ring size, i.e. having both R and R² incorporated in the ring,the cyclization is effected without neutralization of the acid moiety A.

This cyclization reaction is preferably carried out in an inert solventfor the first compound, e.g. a chlorinated organic solvent, such aschloroform, methylene chloride, etc., an ether, e.g. diethyl ether,tetrahydrofuran, etc.

Preferably, a chlorinated organic solvent is used to dissolve the firstcompound, e.g. chloroform or methylene chloride.

To obtain lactams wherein only R is incorporated in the ring, A shouldbe neutralized with a substantially equivalent amount of a base prior tocyclization. (For the purposes of this invention, an equivalent amountof base may vary from 0.8 to 1.2 per equivalent of A. Preferably, theamount of base varies from 0.9 to 1.1 per equivalent of A.)

Thus, the first compound may be mixed with an aqueous solutioncontaining an amount of base substantially equivalent to A and theresulting lactam subsequently extracted with a solvent, e.g. one of theorganic solvents described above. (It should be noted that the identityof A is not limited to acids having a pKa of 0 or more, whencyclization, in the presence of a substantially equivalent amount ofbase, is carried out to obtain lactams wherein only R is incorporatedinto the ring. That is, salts of the first compound and an acid having apKa of less than 0, e.g. hydrochloric acid, may be neutralized with asubstantially equivalent amount of base and then cyclized to a lactamwherein R (only) is incorporated into the ring.)

Alternatively, the first compound may be mixed with water and theresulting mixture stirred in the presence of water-immiscible solventfor the lactam. To this two phase mixture, aqueous base may be slowlyadded whereby the acid is neutralized and dissolves in the aqueous phaseand the resulting lactam dissolves in the water-immiscible solvent.Again, the water-immiscible solvent may be selected from the organicsolvents described above, with the chlorinated solvents such aschloroform and methylene chloride being preferred.

The present process may be carried out at a temperature of from 0° to150° C.; preferably from 0° to 50° C., and a pressure of from 1 to 10atmospheres; preferably from 1 to 5 atmospheres. For convenience,ambient conditions may be used. Preferably, for increased selectivity,the cyclization in the absence of base is carried out at from 25° to 50°C., while cyclization in the presence of a base is carried out at about0° C.

It has been found that the length of the R² moiety affects selectivity,with longer chain lengths favoring the formation of lactams wherein onlyR is incorporated into the ring. Moreover, when the above-defined firstcompound, is prepared as a salt of an acid, e.g. the acetate, it isimportant to immediately carry out the base-catalyzed reaction, if highselectivity to the resulting base catalyzed product is desired. Forexample, when the freshly-prepared acetate salt of 1-ethylamino,1,1-dicaboxylic acid, ethyl ester, 1-methylcarboxylic acid, ethyl estermethane is immediately neutralized with sodium hydroxide, a selectivityto the 5-membered lactam of 75 percent is obtained. However, stirringthe unneutralized salt overnight provides the 6-membered lactam at aselectivity of 97 percent, demonstrating that, when thermodynamicallyfavorable, the first compound will cyclize to the second compound havingthe larger ring size with time.

The invention is further illustrated by the following-examples which areillustrative of various aspects of the invention, and are not intend aslimiting the scope of the invention as defined by the appended claims.

EXAMPLE 1 Preparation of 1-Methyl cyano, 1,1 dicarboxylic acid, ethylester, 1-methylcarboxylic acid, ethyl ester methane

A flame-dried flask was charged with a stirred suspension of 2.0 g (0.05mol) of sodium hydride (60% dispersion in mineral oil); washed free ofoil with 2×20 mL of dry pet ether) in 150 mL of dry tetrahydrofuran(THF) under nitrogen at 0° C. To the suspension, 10 g (0.05 mol) ofethyl 2-carboethoxy-3-cyano propionate was added dropwise and themixture refluxed for 30 min. To the clear solution was added a solutionof 6.1 g (0.05 mol) of ethyl chloracetate in 10 mL dry THF and refluxingwas continued overnight. Water (10 mL) was added and the productextracted with 2×100 mL portions of chloroform. The organic extractswere combined, washed with water, saturated sodium chloride, dried overanhydrous magnesium sulfate, and evaporated. The product was distilledunder high vacuum to give 9.0 g (60%) of a clear colorless oil: bp114°-115° C. (0.2 mm); IR (CHCl₃) 2250, 1740 cm¹ ; NMR (CDCl₃, 60 MHz)4.2 (6H, q), 3.15 (2H, s), 3.05 (2H, s),, 1.25 (9H, t).

EXAMPLE 2 3-(Ethoxycarbonyl)-2-oxo-3-pyrrolidineacetic acid ethyl ester

To a solution of 7.8 g (0.027 mol) of the cyanotriester from Example 1in 75 mL of glacial acetic acid was added 300 mg of platinum (IV) oxide,and the suspension was vigorously agitated under hydrogen (60 psi) for36 h. The mixture was filtered through celite and acetic acid wasremoved under reduced pressure (Ca. 0.5 mm) at 30°-35° C. To theice-cold oily residue was added 100 mL of 1N NaOH in one portion. Themixture was quickly extracted with 3×50 mL dichloromethane and thecombined organic layer was subsequently washed with saturated sodiumchloride solution and dried with magnesium sulfate and solvent wasremoved in vacuo. GC analysis of the crude mixture (injector 300° C.,detector 300° C., column 150° C., program was started after 1 min., 30°C./min to 250° C.) showed 76% of diester-lactam. Upon flashchromatography (silica, 1:1, EtOAc/pet ether), a total of 48 g (73%) ofproduct was obtained as white solid: mp 93°-94° C., IR (CHCl₃) 1735,1700 cm⁻¹ ; NMR (CDCl₃) 6.7 (1H, br), 4.2 (4H, q), 3.6 (1H, m), 3.4 (1H,m), 3.25 (1H, d), 2.85 (1H, m), 2.6 (1H, d), 2.2 (1H, m), 1.25 (6H, t).

Anal. Calcd. for C₁₁ H₁₇ NO₅ : C, 54.31; H, 7.04; N, 5.76. Found: C,54.34; H, 6.89; N, 5.82.

EXAMPLE 3 2-Oxo-4,4-piperidinedicarboxylic acid diethyl ester

To the oily residue from the previous experiment (containing a traceamount of acetic acid) was added 100 mL of chloroform, and the solutionwas stirred at room temperature for 3 days. The chloroform was removedand the residue washed with pet ether, dried over MgSO₄, andconcentrated to give 6.5 g of white solid. GC analysis of crude productover the same conditions described previously showed 97% ofdiester-lactam with a retention time of 4.17 min. Product wasrecrystallized from EtOAc/pet ether to give 6.5 g (95%) of whitecrystalline solid: mp 87°-88° C.; IR (CHCl₃) 1730, 1670 cm⁻¹ ; NMR(CDCl₃) 7.5 (1H, br), 4.2 (4H, q), 3.25 (2H, dt), 2.7 (2H, s), 2.25 (2H,t), 1.25 (6H, t).

Anal. Calcd. for C₁₁ H₁₇ NO₅ : C, 54.31; H, 7.04; N, 5.76. Found: C,54.54; H, 7.19; N, 5.88.

EXAMPLE 4 Preparation of 1-Methyl cyano, 1,1 dicarboxylic acid, ethylester, 1-ethyl carboxylic acid, ethyl ester methane

Alkylation of 20.0 (0.10 mol) of ethyl-2-carboethoxy-3-cyano propionatewith 18.0 g (0.10 mol) of 3-bromopropionate resulted in 29.6 g of crudeoil. Upon flash chromatography (silica, 25% ether/pet ether), andKugelrohr distillation, 22.3 g (74%) of the product isolated as a clearoil: bp 130°-135° C. (0.2 mm); IR (neat) 2250, 1720 cm⁻¹ ; NMR (CDCl₃),60 MHz) 4.15 (6H, m), 2.9 (2H, s), 2.35 (4H, s), 1.3 (9H, t).

Anal. Calcd. for C₁₄ H₂₁ NO₆ : C, 56.18; H, 7.07; N, 4.68. Found: C,55.83; H, 7.08; N, 4.90.

EXAMPLE 5 Hexahydro-7-oxo-4H-Azepine-4,4-dicarboxylic acid diethyl ester

A solution of 14.32 g (47.8 mmol) of the cyanotriester from Example 4 in150 mL of glacial acetic acid was hydrogenated (60 psi) with 250 mg ofplatinum (IV) oxide as described previously. After workup, to the oilresidue was added 200 mL of chloroform and the solution stirred for 3days at room temperature. The solvent was removed in vacuo and theresidue triturated in pet ether (3×50 mL). The solid residue wassubjected to flash chromatorgrphy (silica, EtOAC) to give white solid:mp 80°-81° C.; IR (CHCl₃) 1725, 1665 cm⁻¹ ; NMR (CDCl₃, 250 MHz) 6.15(1H, br), 4.19 (4H, q, J=7.2 Hz), 3.3 (2H, m), 2.48 (2H, m), 2.28-2.12(4H, m), 1.24 (6H, t, J=7.2 Hz).

Anal. Calcd. for C₁₂ H₁₉ NO₅ : C, 56.02; H, 7.44; N, 5.44. Found: C,55.80; H, 7.39; N, 5.38.

EXAMPLE 6 3-(Ethoxycarbonyl)-2-ones-4-pyrrolidinebutyric acid diethylester

To the oily residue from previous experiment was added base andextracted as described before to give the pyrrolidinediester with aR_(f) of 0.37 (silica,, EtOAc). After flash chromatography the productwas obtained as white solid: mp 57°-58° C.; IR (CHCl₃) 1740-1700 cm⁻¹ ;NMR (CDCl₃);, 250 MHz) 6.6 (1H, br), 4.19 (2H,, q, J=7.3 Hz), 4.10 (2H,q, J=7.3 Hz), 3.43 (1H, m), 3.32 (1H, m), 2.56 (1H, m), 2.45 (1H, m),2.31 (2H, m), 2.06 (2H, m), 1.25 (3H, t, J=7.3 Hz), 1.23 (3H, t, J=7.3Hz.)

Anal. Calcd. for C₁₂ H₁₉ NO₅ : C, 56.02; H, 7.44; N, 5.44. Found: C,55.80; H, 7.39; N, 5.38.

EXAMPLE 7 Preparation of 1-Methylcyano, 1,1 dicarboxylic acid, ethylester, 1-n-propyl carboxylic acid, ethyl ester methane

Alkylation of 20 g (0.10 mol) of ethyl-2-carboethoxy-3-cyano propionatewith 19.5 g (0.1 mol) of ethyl 4-bromobutyrate resulted in 38.5 g ofcrude oil. Upon fractional distillation, product was obtained as a clearoil: bp 150°-165° C. (0.4 mm), IR (neat) 2250, 1740 cm⁻¹, NMR (CDCl₃)4.0 (6H, m), 2.8 (2H, s). 2.3-1.3 (6H, m), 1.2 (3H, t).

Anal. Calcd. for C₁₅ H₂₃ NO₆ : C, 57.50; H, 7.40; N, 4.47. Found: C,57.78; H, 7.27; N, 4.98.

EXAMPLE 8 3-(Ethoxycarbonyl)-2-oxo-5-pyrrolidinevaleric acid diethylester

A solution of 10 g (32 mmol) of the cyanotriester from Example 7 in 80mL of glacial acetic acid was hydrogenated (60 psi) with 250 mg ofplatinum (IV) oxide as described previously. After workup, to the oilyresidue was added 200 mL of chloroform and the solution stirred for 3days at room temperature. The solvent was removed in vacuo and theresidue was subjected to flash chromatography (silica, 75% ethylacetate/hexane) to yield 6.54 g (75%) of a white solid: mp 72°-73° C.;IR (CHCl₃) 1740-1700 cm⁻¹ ; NMR (CDCl₃, 250 MHz) 6.4 (1H, br), 4.18 (2H,q, J=7.2 Hz), 4.10 (2H, q, J=7.2 Hz), 3.45 (1H, m), 3.31 (1H, m), 2.61(1H, m), 2.33 (2H, m), 2.08 (2H, m), 1.66 (3H, m), 1.25 (3H, t, J=7.2Hz), 1.23 (3H, t, J=7.2 Hz).

While particular embodiments of the invention have been described itwill be understood of course that the invention is not limited theretosince many obvious modifications can be made and it is intended toinclude within this invention any such modifications as will fall withinthe scope of the appended claims.

What is claimed is:
 1. A process for converting a first compoundrepresented by the general formula: ##STR4## into a second compoundrepresented by the general formula: ##STR5## wherein R represents analkylene or alkenylene radical containing 1 or 2 carbon atoms; R¹ is analkyl radical having from one to eight carbon atoms; R² is selected fromradicals represented by the general formula --CR⁴ 2)_(y) wherein R⁴ isselected from the group consisting of hydrogen, alkyl radicals having 1to 6 carbon atoms and phenyl; y is an integer of 1 or 2; and A is anacid selected from the group consisting of carboxylic acids havingbetween 1 and 10 carbon atoms, which process comprises the step ofcyclizing said first compound under anhydrous conditions at a neutral oracidic pH, in the absence of a base, and in the presence of an inertsolvent at a temperature sufficient to cause cyclization to the five,six and/or seven membered ring lactam.
 2. The process of claim 1 whereinR⁴ is hydrogen, x is 2 and y is 1 or
 2. 3. The process of claim 2wherein R¹ is ethyl.
 4. The process of claim 3 wherein y is
 1. 5. Theprocess of claim 1 wherein said first compound is cyclized by stirringin a solution of an inert organic solvent.
 6. The process of claim 5wherein said inert organic solvent is an alkyl chloride.
 7. The processof claim 6 wherein said first compound is reacted by stirring a solutionthereof in a chloroform solvent at room temperature.
 8. The process ofclaim 1 wherein said carboxylic acid is acetic acid.